The microphthalmia-associated transcription factor (MITF) was identified as the product of a gene that affects murine coat color. The MITF gene encodes a basic-helix-loop-helix leucine zipper (bHLH-ZIP) transcription factor that homo- or heterodimerizes with the related transcription factors: TFEB, TFE3 and TFEC. These transcription factors, collectively termed the MiT family of transcription factors, are more ubiquitously expressed and unlike MITF are not essential for melanocytic differentiation (6). However, all members of the MiT family bind via their basic domains to identical DNA target sequences containing the canonical E-box promoter element CACGTC or the non-palindromic sequence CACATG.
When its activity is up-regulated in normal melanocytes, MITF initiates a transcriptional program leading to melanocyte differentiation, cell cycle arrest, and survival. It has also been suggested that MITF may induce cell cycle arrest during melanocytic differentiation, potentially via transcriptional targeting of the cyclic dependent kinase inhibitors p21, CDKN1A (13) and CDK4A (INK4A) (14). The anti-apoptotic protein Bcl-2 is directly activated by MITF and supports the survival of melanocytes since Bcl-2 knockout results in white coat-color due to melanocyte death (15).
A role for MITF in melanocyte survival is further supported by the consequence of MITF mutation in mice and people: melanocyte death, rather than presence of unpigmented melanocytes. Correspondingly, amplification and over-expression of MITF occurs in 15-20% of melanomas, leading to its designation as a bona fide melanoma oncogene (1). Suppression of MITF activity is lethal to melanomas, and high MITF expression is a poor prognostic factor in melanoma patients, as MITF over-expression is associated with a decrease in 5-year overall survival. Moreover, enforced MITF overexpression was shown to cooperate with the common melanoma oncogene BRAF(V600E) to transform human melanocytes (1). These results indicate that MITF can have either differentiative or tumorigenic effects depending on the cellular context. Whereas physiologic activation of Bcl-2 expression may protect melanocytes (for example, from ultraviolet light), its up-regulation in the context of melanoma may actually contribute to this cancer's notorious chemoresistance.
The above results suggest that small molecule compounds that suppress MITF would be useful not only in understanding the biology of context-specific transcriptional control, but also for developing therapeutic strategies for cancer, such as melanoma. With the exception of nuclear hormone receptors, success in directly targeting transcription factors has been very limited (16). Therefore, the identification of upstream druggable pathways that regulate MITF would be important as an alternative therapeutic strategy.